Discovery of 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9H-pyrrolo[2,3-b:4,5-c’]dipyridine ([18F]PI-2014) as PET tracer for the detection of pathological aggregated tau in Alzheimer’s disease and other tauopathies

PI-2620 Lead Optimization Highlights the Importance of Off-Target Assays to Develop a PET Tracer for the Detection of Pathological Aggregated Tau in Alzheimer’s Disease and Other Tauopathies

“…For compound PI-2014, we observed delayed brain uptake and slow and incomplete brain washout in rhesus monkey, leading to a significant background signal in human with off-target binding in substantia nigra, basal ganglia, and choroid plexus, similar to what was observed for AV-1451 (T807, flortaucipir). 17 We hypothesized that the PK profile observed in rhesus monkey could be due to the MAO-A off-target binding of PI-2014, which was determined in a luminescence-based MAO-Glo functional assay with an IC 50 of 128 nM. 17 We identified the pyrrolo[2,3b:4,5-c′]dipyridine core structure from PI-2014 as a starting point for lead optimization as this core may have an intrinsic affinity to bind to MAO-A due to its structural similarity to the pyrido [3,4-b]indole tricyclic core present in the reversible MAO-A binder harmine (K d = 2.0 nM).…”

“…17 We hypothesized that the PK profile observed in rhesus monkey could be due to the MAO-A off-target binding of PI-2014, which was determined in a luminescence-based MAO-Glo functional assay with an IC 50 of 128 nM. 17 We identified the pyrrolo[2,3b:4,5-c′]dipyridine core structure from PI-2014 as a starting point for lead optimization as this core may have an intrinsic affinity to bind to MAO-A due to its structural similarity to the pyrido [3,4-b]indole tricyclic core present in the reversible MAO-A binder harmine (K d = 2.0 nM). 18 Thus, the aim was to improve the selectivity of Tau-versus MAO-A binding of our compounds and their Tau binding as PI-2014 displayed binding to PHF with an IC 50 of 26 nM.…”

“…18 Thus, the aim was to improve the selectivity of Tau-versus MAO-A binding of our compounds and their Tau binding as PI-2014 displayed binding to PHF with an IC 50 of 26 nM. 17 To evaluate Tau binding, human brain homogenates from post-mortem AD patients were employed. We did not use synthetic Tau aggregates as they do not contain posttranslational modifications and might not recapitulate the specific conformation found in human AD-derived Tau aggregates.…”

“…The slow brain washout of PI-2014 in human AD patients resulted in a significant background signal, leading to a low target/reference region ratio. 17 Herein, we report our efforts to overcome the limitations of PI-2014 by addressing significant MAO-A off-target binding, significant background signal in non-human primate (NHP) PET, and to further increase binding specificity to Tau aggregates, leading to the discovery of PI-2620…”

Positron Emission Tomography in Animal Models of Tauopathies

“…Among the other second-generation tau tracers, [ 18 F]JNJ-64349311 (Declercq et al, 2017) and [ 18 F]PI-6240 (Kroth et al, 2019) have so far been reported in wild-type mice for brain uptake and biodistribution assessment. In addition, several new tau probes are underdevelopment such as [ 18 F]IBIPF1 (Kaide et al, 2019), [ 18 F]PI-2014 (Gabellieri et al, 2020), [ 18 F]PPQ (Lerdsirisuk et al, 2021), [ 11 C]LM229 (McMurray et al, 2021), [ 18 F]2-phenylquinoxaline derivatives (Zhou K. et al, 2021), antibody-based imaging (Krishnaswamy et al, 2014), and 4R-tau specific tracer [ 18 F]CBD-2115 (Lindberg et al, 2021). Maruyama et al, 2013;Ishikawa et al, 2018;Ni et al, 2018;Takuwa et al, 2020PS19 mice Maruyama et al, 2013Barron et al, 2020;Fairley et al, 2021;Ji et al, 2021 [ 18…”